title: Skeletal muscle-specific T-tubule protein STAC3 mediates voltage-induced Ca2+ release and contractility.
abstract: Excitation-contraction (EC) coupling comprises events in muscle that convert electrical signals to Ca(2+) transients, which then trigger contraction of the sarcomere. Defects in these processes cause a spectrum of muscle diseases. We report that STAC3, a skeletal muscle-specific protein that localizes to T tubules, is essential for coupling membrane depolarization to Ca(2+) release from the sarcoplasmic reticulum (SR). Consequently, homozygous deletion of src homology 3 and cysteine rich domain 3 (Stac3) in mice results in complete paralysis and perinatal lethality with a range of musculoskeletal defects that reflect a blockade of EC coupling. Muscle contractility and Ca(2+) release from the SR of cultured myotubes from Stac3 mutant mice could be restored by application of 4-chloro-m-cresol, a ryanodine receptor agonist, indicating that the sarcomeres, SR Ca(2+) store, and ryanodine receptors are functional in Stac3 mutant skeletal muscle. These findings reveal a previously uncharacterized, but required, component of the EC coupling machinery of skeletal muscle and introduce a candidate for consideration in myopathic disorders.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Nelson
authors.forename: Fenfen
authors.initials: F
authors.lastname: Wu
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Anderson
authors.forename: John
authors.initials: J
authors.lastname: McAnally
authors.forename: Weichun
authors.initials: W
authors.lastname: Lin
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Cannon
authors.forename: Rhonda
authors.initials: R
authors.lastname: Bassel-Duby
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
mesh_terms: D000200:Action Potentials / Q000502:physiology; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D018274:Electroporation; D005838:Genotype; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009119:Muscle Contraction / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction; D001616:beta-Galactosidase
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; D009419:Nerve Tissue Proteins; C583601:STAC3 protein, mouse; D001616:beta-Galactosidase; D002118:Calcium
keywords: dihydropyridine receptor; dysgenic; dyspedic; myopathy; neuromuscular junction